Pharmaceutical compositions comprising paracetamol and L-cysteine or a precursor thereof

ABSTRACT

An improved process for the production of a pharmaceutical composition comprising p-hydroxyacetanilide and L-cysteine or a compound which is converted thereto in vivo comprises mixing p-hydroxyacetanilide and L-cysteine or its precursor in the solid state and then shaping the solid mixture.

This application is a 371 of PCT/GB94/00446, filed Mar. 8, 1994, whichclaims priority to UK 93050581, filed Mar. 12, 1993.

This invention relates to analgesics and in particular to novelformulations of p-hydroxyacetanilide.

p-Hydroxyacetanilide or paracetamol finds wide use as an analgesic andhas the particular advantage of having a relatively pure analgesicaction with few side effects when used in normal dosages. However,overdoses of the drug can be very toxic and the ready availability ofthe drug has led to its use on a quite significant scale as a means ofattempting suicide. Even when the overdose is not fatal it can lead tosevere liver injury and the methods at present available for thetreatment of an overdose of the drug are often ineffective in preventingthis.

This problem has been recognised for a considerable time and in 1973, UKPatent Application 54098/73 was filed (published as UK Patent 1,463,505)describing a means of overcoming the problem. Thus, the toxicity ofp-hydroxyacetanilide is due to the hepatic necrosis induced by a toxicmetabolite to which the drug is converted in vivo. However, the compoundglutathione, which is a tripeptide containing a central L-cysteine unit,is in some way involved with the toxic action of the metabolite in thebody so that only when the liver has been depleted of glutathione doessignificant hepatic necrosis occur. Formulation of p-hydroxyacetanilidetogether with L-cysteine or a compound which is converted thereto invivo has the very great advantage that an overdose of the drugautomatically results in an increase in the amount of glutathionesynthesised by the body thus countering the toxic effect of theoverdose. The glutathione precursor may also detoxify thep-hydroxyacetanilide by providing intracellular sulphate, the formationof its sulphate being an alternative safe metabolic pathway for thedisposal of p-hydroxyacetanilide.

However, although a product (Pameton) has for some time been availablein the United Kingdom which avoids the dangers of overdose through theinclusion together with p-hydroxyacetanilide of the L-cysteine precursorDL-methionine, the major part of the market for p-hydroxyacetanilide isstill met by products which provide no protection against an overdose.This is in significant measure due to the characteristic sulphur typeodour which is associated with the marketed product that providesprotection against an overdose, as discussed in UK Patent 1,583,602. Ithas now been found that it is possible to solve the problem of thepotential extreme toxicity of overdoses of p-hydroxyacetanilide throughformulating this compound together with DL-methionine or like compoundin a manner which does not produce a product with a marked sulphur typeodour, thereby providing a much more acceptable product which issuitable for the general market.

According to the present invention a process for the production of apharmaceutical composition comprising p-hydroxyacetanilide andL-cysteine or a compound which is converted thereto in vivo comprisesmixing p-hydroxyacetanilide and L-cysteine or its precursor in the solidstate and then converting the solid mixture to a shaped product.

The term "shaped" is used herein in its normal sense of having a definedform as, for example, in a tablet, and "shaping" is used to indicate theproduction of such a defined form.

The problems of producing a shaped or formed product comprisingp-hydroxyacetanilide are discussed in UK Patent 1,390,032 where it isindicated that a granular material must be employed for this purpose.Further attention is paid in UK Patent 2,124,078 and its equivalentEuropean Patent Application A-0 100 168 to the problem of producing ashaped composition of p-hydroxyacetanilide, including one containingmethionine, and the use of a wet-granulation technique is proposed. Thefinal composition obtained by such techniques may not necessarilycontain a significant amount of water but the defect of these prior artprocesses is that their initial stages involve a wet process, theproduction of the marketed product Pameton also involving such aprocess. Without limitation to any particular mode of operation, it isbelieved that one advantage of the present invention over the prior artlies in the avoidance of hydrolysis of the L-cysteine or its precursorwith the formation of volatile sulphur-containing products.

Thus, it has now been found that it is possible to produce a solidpharmaceutical composition comprising p-hydroxyacetanilide andDL-methionine or like compound through shaping a solid mixture which isproduced through admixture of the components in the solid state and thatthe composition, although not odourless, has a more acceptable odourthan that of a composition derived from a granular product obtained by awet process. In addition to this primary advantage the product producedby the dry process of the present invention has the further advantage ofcontaining a high amount of p-hydroxyacetanilide per unit volume so thatthe size of a tablet containing a unit dosage of 500 mgp-hydroxyacetanilide is readily acceptable to the patient. The findingthat p-hydroxyacetanilide and L-cysteine or a compound which isconverted thereto in vivo can be directly formulated, particularly bydirect compression, into a shaped pharmaceutical composition is all themore surprising in the light of the conventional view, as expressed inUK Patent 1,390,032, that the formulation of p-hydroxytacetaniliderequires a granulation step.

In one aspect the present invention thus includes a solid mixturesuitable for use in the manufacture of a shaped pharmaceutical productcomprising p-hydroxyacetanilide and L-cysteine or a compound which isconverted thereto in vivo characterised in that the mixture is ofnon-granular form.

In a further aspect the present invention includes a solid mixturecomprising p-hydroxyacetanilide and L-cysteine or a compound which isconverted thereto in vivo characterised in that the L-cysteine or itsprecursor is substantially of a particle size less than 1,000 microns.

Thus, it has been found that of the two major components, it is thephysical form of L-cysteine or its precursor rather than that of thep-hydroxyacetanilide which is most relevant to an improvement of theprior art procedures for the formulation of the pharmaceuticalcomposition. In particular the ease of producing a pharmaceuticalcomposition according to the invention is enhanced through the use ofL-cysteine or its precursor in a form substantially of a particle sizewhich is less than 1,000 microns and conveniently less than the standardsieve size of 710 microns. By the phrase "substantially of a particlesize" it is meant that a proportion by weight of at least 80 percent isof the size indicated, although preferably at least 90 percent andconveniently essentially 100 percent may be of the size indicated. Therequirement as to a minimum particle size is less critical. However,conveniently less than 50 percent by weight and particularly less than30 percent by weight of the L-cysteine or its precursor is of a particlesize less than 250 microns.

It is preferred that a proportion of the L-cysteine or its precursor ofat least 50% by weight, conveniently of at least 60% by weight andparticularly of at least 70% by weight, is of a particle size in therange of 250 to 1,000 microns and conveniently of 250 to 710 microns.

It may be necessary to mill the commercially available sample of theL-cysteine-providing component of the composition to conform to thepreferred particle size requirements indicated above. This is usuallythe case, for example, with DL-methionine but not with L-methionine. Thesize of the p-hydroxyacetanilide component of the mixture is of lesssignificance and a commercially available sample may be suitable fordirect use. Commonly, the particle size of such a sample may, forexample, be such that a proportion of 50 to 60 percent by weight has aparticle size of between 53 and 150 microns. If required, however, thematerial may be subjected to a simple screening procedure before use toensure that it is substantially of a particle size less than aparticular amount, for example 1,000 or particularly 710 microns. Thephrase "substantially of a particle size" has the same meaning aspreviously and the same further preferences apply, i.e. preferably atleast 90 percent by weight and conveniently essentially 100 percent byweight being of the size indicated.

In order to provide a pharmaceutical composition according to theinvention which has an acceptable odour it is preferred that the amountof water in the composition is no more than 2.5 or 2.0 percent by weightof the whole, preferably no more than 1.5 or 1.0 percent andconveniently no more than 0.8 percent. Although the compositiontherefore preferably consists of essentially dry materials, the presenceof some water is desirable for effective binding, so that thecomposition preferably includes an amount of water which is at least 0.4percent by weight of the whole, preferably at least 0.5 percent andconveniently at least 0.6 percent.

The proportion by weight of water present in a pharmaceuticalcomposition produced by the process of the present invention is thuspreferably in a range from 0.4 or 0.5 to 2.5 percent by weight of thewhole, with further preferences as to the upper and lower limits beingas previously indicated, a particularly preferred range being from 0.5to 1.0 percent, conveniently from 0.6 to 0.8 percent, for example 0.7percent.

The amount of water present prior to the shaping of the composition willgenerally conform to the figures indicated for the composition as thereis usually no significant change in water content involved in theprocess of shaping the mixture of compounds. The figures quoted forwater content herein are those obtained by measurement using the KarlFischer technique. This involves the use of a solution of iodine andsulphur dioxide in pyridine/methanol to titrate water. The reagent iscommercially available.

As regards the L-cysteine-providing component of the pharmaceuticalcomposition, either L-cysteine or any compound which is metabolised bythe body to provide L-cysteine may be used. It will be appreciated thatthe compound need not necessarily all be converted to L-cysteine norneed all the L-cysteine be converted into glutathione. The function ofthis component is, in the event of an overdose of the drug being takenand the normal supply of glutathione in the body being exhausted, toprovide a replacement source of L-cysteine.

In addition to L-cysteine itself, the naturally occurring amino acids ofparticular interest are L-cystine and particularly L-methionine,L-methionine being preferred to L-cysteine itself. The DL isomer of thesulphur-containing amino acids can also be used and in the case ofmethionine but not of cysteine both the D and L isomers provide a sourceof the L-cysteine component of glutathione. A D isomer may alsocontribute by the provision of intracellular sulphate. An L isomer andin particular L-methionine does have the advantage of greater purity andpossibly of being available in a form having a particle size range whichis acceptable for immediate use thereby avoiding the necessity ofmilling.

If desired, larger molecules such as di-, tri- or higher peptides whichbreak down in vivo to give L-cysteine may be used, a particularlysuitable type of dipeptide being one which provides two of the aminoacid units of glutathione, i.e. L-glutamyl-L-cysteine orL-cysteinyl-glycine. Preferably however L-cysteine or another amino acidis used.

It will be appreciated that the L-cysteine-providing component may ifdesired be in the form of a salt with any physiologically acceptableacid or base. Thus, salts may be formed with various suitable inorganicand organic acids. Examples of such inorganic acids are phosphonic acid,nitric acid, sulphuric acid and particularly the hydrohalic acidshydrochloric acid, hydrobromic acid and hydroiodic acid. Examples ofsuch organic acids are citric acid, oxalic acid, fumaric acid, maleicacid, lactic acid, succinic acid, malic acid, tartaric acid and methanesulphonic acid. Alternatively salts may be formed with various suitableinorganic and organic bases. Examples of these are the alkali metalhydroxides, for example sodium hydroxide, quaternary ammonium hydroxidesand amines such as tris (tris representing 2-amino-2-hydroxymethylpropane 1,3-diol).

As regards the relative proportion of L-cysteine or its precursor andp-hydroxyacetanilide the major consideration is the provision of asufficient supply of glutathione to counter toxicity in the event of anoverdose of p-hydroxyacetanilide depleting the normal supply ofglutathione. However, it is not desirable to include an unnecessarilylarge proportion of the L-glutathione providing compound. The proportionof this compound by weight relative to the p-hydroxyacetanilide will ofcourse vary depending particularly upon the nature of the compound usedbut an amount in the range from 5 to 100%, conveniently 10 to 50%, andpreferably 15 to 25%, for example 20%, is usually suitable.

In addition to p-hydroxyacetanilide and L-cysteine or its precursor, thecomposition may, if desired, contain other active ingredients, forexample one or more of the compounds caffeine, caffeine hydrate,codeine, codeine phosphate, dihydrocodeine tartrate, pseudoephidrinehydrochloride and phenolphthaline. Of these compounds codeine and/orcaffeine in one form of another are most usually formulated togetherwith p-hydroxyacetanilide. It will be appreciated, however, that thepresent formulation will not counter any toxic effects arising fromoverdoses of these other ingredients. However, these effects may not beas severe as those arising from the p-hydroxyacetanilide andcompositions additionally containing codeine or a salt thereof are ofparticular interest. In addition to its active ingredients apharmaceutical composition produced according to the present inventionwill usually contain a physiologically acceptable solid carrier.

The present invention thus includes a shaped pharmaceutical compositioncomprising a non-granular solid mixture comprising p-hydroxyacetanilideand L-cysteine or a compound which is convertible thereto in vivotogether with a physiologically acceptable solid carrier.

Moreover, the present invention further includes a pharmaceuticalcomposition comprising a solid mixture of p-hydroxyacetanilide andL-cysteine or a compound which is converted thereto in vivocharacterised in that the L-cysteine or its precursor is substantiallyof a particle size less than 1,000 microns.

A carrier material used in a pharmaceutical composition according to thepresent invention may be conventional to the art of pharmaceuticalformulation but such materials are preferably selected in both natureand quantity with a view to producing particular physical properties forthe composition. Thus, for example, the composition may convenientlycontain one or more of a component which acts as a lubricant for flow ofthe various components together, a component which enhances adhesion ofthe components of the composition during shaping, and a component whichaids dispersion of the composition in the body. Among these, thepresence of an adhesive agent is of especial interst. Of particularvalue as a lubricant is a starch product such as sodium starchglycollate, for example Explotab; as an adhesive agent is a vinylpolymer, particularly an N-vinyl polymer such as polyvinylpyrrolidone,together with a cellulose product such as microcrystalline cellulose,for example Avicel PH102, which not only aids adhesion throughconferring mechanical strength but which also exerts a wicking effectthereby aiding the action of the dispersing agent; and as a dispersingagent is magnesium stearate. These components may be present inconventional proportions, for example an amount by weight of the wholecomposition equal to 0.5 to 2 percent of sodium starch glycollate, forexample 0.96 percent, 2 to 8 percent of polyvinylpyrrolidone, forexample 4.08 percent, 0.15 to 0.6 percent of cellulose, for example 0.32percent, and 0.7 to 3 percent of magnesium stearate, for example 1.44percent, or a similar amount of an alternative to these materialsperforming a similar function.

The process of the present invention involves admixture of the variouscomponents, conveniently in an order commencing with the activeingredients followed by the carrier materials. However, thep-hydroxyacetanilide mixed with the L-cysteine or its precursor mayconveniently be in a form in which it is already coated with the primaryadhesive agent such as polyvinylpyrrolidone (p-hydroxyacetanilide beingcommercially available in such a coated form).

The advantage of using L-cysteine or its precursor in a physical formwith a particular particle size has been discussed previously but thecarrier materials, like the p-hydroxyacetanilide, may often be used inthe physical form as supplied in the usual commercial samples of thematerial or alternatively may be subjected to a simple screeningprocedure to remove particles above 1,000 or particularly 710 microns.It will often be the case therefore that the whole mixture including thep-hydroxyacetanilide and the carrier materials conforms to the mainpreference indicated for the L-cysteine or its precursor so that it issubstantially of a particle size which is less than 1,000 microns andconveniently less than 710 microns.

Following admixture, suitably using conventional techniques, the mixtureis shaped or formed, particularly by compression using a suitable levelof pressure. A conventional compression machine may be used and thiswill usually effect a degree of compression which produces a level ofhardness in the range of about 5 to 12 kilopascals, for example 5 to 7kilopascals. The shaped product will generally have the form of atablet, conveniently with either an essentially circular cross sectionor an elliptical cross section with a length greater than its width.After shaping the product may be treated further as desired, for exampleto provide a coating which will assist in preventing the take up ofmoisture during storage. Such a coating may consist of wax oralternatively of a film forming polymer such as an acrylic polymer, forexample the aminoalkyl methacrylate copolymer marketed under the tradename EUDRAGIT E100.

The compositions may conveniently be formulated in unit dosage form,i.e. in the form of discrete portions each containing a unit dose, or amultiple or sub-multiple of a unit dose, of p-hydroxyacetanilide.

The recommended daily dose of p-hydroxyacetanilide for an adult humanpatient is of the order of from about 1.5 to about 4 grams daily, asrequired, usually being divided into 3 or 4 spaced doses of from about0.5 to about 1 gram and with the dose being approximately halved forchildren. Conveniently, therefore, individual tablets contain from 0.1to about 2 grams, preferably from about 0.25 to about 0.75 or 1 gram andusually 0.5 grams. Veterinary doses are on a similar mg/kg basis but thepresent invention is of particular application to the production ofpharmaceutical compositions for human use.

p-Hydroxyacetanilide is of value for use not only as an analgesic butalso in other contexts, particularly as an antipyretic.

The present invention thus includes the use of a non-granular solidmixture comprising p-hydroxyacetanilide and L-cysteine or a compoundwhich is converted thereto in vivo for the manufacture of a medicamentfor use as an analgesic or antipyretic.

Moreover, the present invention further includes the use of a solidmixture comprising p-hydroxyacetanilide and L-cysteine or a compoundwhich is converted thereto in vivo in which the L-cysteine or itsprecursor is substantially of a particle size less than 1,000 micronsfor the manufacture of a medicament for use as an analgesic orantipyretic.

Also included by the present invention is a method for the treatment ofa patient in need thereof, for example a patient requiring analgesic orantipyretic treatment, with a therapeutically effective amount of apharmaceutical composition as described herein.

It will be appreciated that the present invention further includes anynew process for the production of a pharmaceutical compositioncomprising p-hydrodyacetanilide and L-cysteine or a compound which isconverted thereto in vivo, and also any such new a pharmaceuticalcomposition, as is described hereinbefore.

The invention is illustrated by the following examples.

EXAMPLES Example 1 Production of Composition of p-Hydroxyacetanilide andDL-Methionine

DL-Methionine was milled before use using either a Fitzmill or adispersion mill in order to reduce the particle size of the commercialsample. Analysis of a typical milled sample shows the followingdistribution by weight on passing the material through a succession ofstandard sieves of decreasing size:

    ______________________________________                                        0.83%       retained on 710 micron sieve;                                     63.6%       retained on 300 micron sieve;                                     18.2%       retained on 250 micron sieve;                                     10.76%      retained on 150 micron sieve;                                     4.96%       retained on 106 micron sieve, and                                 1.65%       remaining.                                                        ______________________________________                                    

p-Hydroxyacetanilide was treated with a solution of polyvinylpyrrolidoneand dried in a fluid bed drier. (Such a coated material is commerciallyavailable.) The coated material was passed through a 710 micron sieve.

The DL-methionine (1556.49 g) was transferred into a 20 kg drum whichhad been cleaned and dried and the polyvinylpyrrolidone-treatedp-hydroxyacetanilide (paracetamol, sieved D.C. grade, 95%p-hydroxyacetanilide and 5% polyvinylpyrrolidone by weight) (8171.60 g)was added to the drum. The drum was placed on an adapted WinkworthTurbula Blender and blending carried out for 10 minutes at 44 rpm.

Sodium starch glycollate (Explotab) (96.19 g) and microcrystallinecellulose (Avicel PH102) (31.59 g) were manually mixed in a cleandouble-lined polythene bag with approximately the same weight (127.78 g)of the blend of p-hydroxyacetanilide and methionine taken from theBlender. The mixture from the bag was then added to the remainder of theblend of p-hydroxyacetanilide and methionine in the Blender and thewhole blended for 10 minutes at 44 rpm.

Magnesium stearate (158.54 g) was passed through a 710 micron mesh sieveand 144.13 g of the sieved material was added to a clean double-linedpolythene bag. To the bag was then added approximately double the weight(288.26 g) of the blend of p-hydroxyacetanilide, methionine, sodiumstarch glycollate and microcrystalline cellulose from the Blender, thewhole then being manually mixed in the bag for 3 minutes. The mixturefrom the bag was then added to the remainder of the blend of the othercomponents in the Blender and the whole blended for 5 minutes at 44 rpm.

The bulk powder blend was transferred into double-lined polythene bagswhich were in turn placed, prior to tabletting, in lidded whitepolycarbonate pots laden with an ample supply of dessicant sachets. Thepowder was compressed into tablets in amounts of approximately 10,000 gusing a Manesty-D3-B compression machine providing a hardness of 5 to 7kilopascals. The target mass per tablet was 642.47 mg with theindividual mass being within the ±5% target range of 611-674 mg. Thesetablets were placed in a coating pan which was then rotated. Beeswax(150 g) was dissolved in slightly warm industrial methylated spirit(IMS) (3 liters) at about 30° C. and 200 ml of the warm solution wassprayed from a spray container onto the rolling tablets in the coatingpan. The tablets were allowed to polish for 5 to 10 minutes and werethen packaged.sup.(1).

In odour tests the tablets, although typically not completely odourless,possessed an odour much more acceptable to the human nose than thecommercial product Pameton.

Example 2 Production of Composition of p-Hydroxyacetanilide andL-Methionine

The procedure of Example 1 was repeated exactly but replacing the1556.49 g of DL-methionine by the same weight of L-methionine which didnot, however, require milling before use.

I claim:
 1. A process for the production of a pharmaceutical compositioncomprising p-hydroxyacetanilide and L-cysteine or a compound which isconverted thereto in vivo which process comprises mixingp-hydroxyacetanilide and L-cysteine or its precursor in the solid stateand then converting the solid mixture to a shaped product, wherein (i)the mixing and converting to a shaped product do not involve a wetgranulation step, (ii) the L-cysteine or its precursor is substantiallyof a particle size less than 1,000 microns, and (iii) the shaping is bydirect compression.
 2. A process according to claim 1, in which thesolid mixture is non-granular.
 3. A process according to claim 1, inwhich the composition additionally comprises a physiologicallyacceptable solid carrier which is mixed with the p-hydroxyacetanilideand L-cysteine or its precursor in the solid state prior to shaping ofthe mixture.
 4. A process according to claim 3, in which the carriercomprises the adhesive agent polyvinylpyrrolidone.
 5. A processaccording to claim 1, in which the amount of water in the solid mixtureis in the range of 0.5 to 2.5 percent by weight of the whole.
 6. Aprocess according to claim 1, in which p-hydroxyacetanilide andDL-methionine or a physiologically acceptable salt thereof are mixed inthe solid state and then converted to a shaped product.
 7. A processaccording to claim 1, in which p-hydroxyacetanilide and L-methionine ora physiologically acceptable salt thereof are mixed in the solid stateand then converted to a shaped product.